Anti-hyperlipidemic drugs


Anti-hyperlipidemic drugs


These are drugs which lower the levels of lipids and lipoproteins in blood.


The hypolipidaemic drugs have attracted considerable attention because of their potential to prevent cardiovascular disease by retarding the accelerated atherosclerosis in hyperlipidaemic individuals.



 1. HMG-CoA reductase inhibitors (Statins): Lovastatin, Simvastatin, Pravastatin, Atorvastatin, Rosuvastatin, Pitavastatin

2. Bile acid sequestrants (Resins): Cholestyramine, Colestipol


3. Lipoprotein lipase activators (PPARα activators, Fibrates): Clofibrate, Gemfibrozil, Bezafibrate, Fenofibrate.

4. Lipolysis and triglyceride synthesis inhibitor: Nicotinic acid.


5. Sterol absorption inhibitor: Ezetimibe.




Introduced in the 1980s, these classes of compounds are the most efficacious and best tolerated hypolipidaemic drugs. 

They competitively inhibit conversion of HMG-Coto mevalonate by the enzyme HMG-CoA reductase. 

Therapeutic doses reduce CH synthesis by 20–50%. 

This results in compensatory increase in LDL receptor expression on  liver  cells   increased receptor  mediated  uptake  and catabolism of IDL and LDL. 

Over long-terinduction of HMG-CoA reductase tends to increase CH synthesis, but a steady-state is finally attained with a dosedependent lowering of LDL-CH levels.

Different statins differ in their potency and maximal efficacy in reducing LDL-CH

The daily dose for lowering LDL-CH by 30–35% is lovastatin 40 mg, pravastatin

40 mg, simvastatin20 mg, atorvastatin 10 mg, rosuvastatin 5 mg and pitavastatin 2 mg. 

Moreover, at their maximum recommended doses simvastatin (80 mg) causes

45–50% reduction, while atorvastatin (80 mg) and rosuvastatin (40 mg) can reduce LDL-CH by upto 55%. The ceiling effect of lovastatin and pravastatin is 3040% LDL-CH reduction. 

All statins produce peak LDL-CH lowering after 1–2 weeks therapy. 

Hepatic synthesis of VLDL is concurrently reduced and its removal from plasma is enhanced.

Because HMG-CoA reductase activity is maximum at midnight, all statins are administered at bed time to obtain maximum effectiveness. 

However, this is not necessary for atorvastatin and rosuvastatin, which have long plasma t½. 

All statins, except rosuvastatin are metabolized primarily by CYP3A4. 

Inhibitors and inducers of this isoenzyme respectively increase and decrease statin blood levels


It is the first clinically used statin; is lipophilic and given orally in the precursor lactone form. 

Absorption is incomplete and first pass metabolism is extensive. 

Metabolites are excreted mainly in bile. The is short (1–4 hours)

Simvastatin: It is twice as potent as lovastatin; also more efficacious. 

A greater rise in HDLCH (when low) has been noted with simvastatin than lovastatin or pravastatin. 

Like lovastatin, it is lipophilic and given in the lactone precursor form

Oral absorption is better and first pass metabolism extensive; is 2–3 hr


This newer and most popular statin is more potent and appears to have the highest LDL-CH lowering efficacy at maximal daily dose of 80 mg. 

At this dose a greater reduction in TGs is noted if the same was raised at baseline

Atorvastatin has a much longer plasma of 18 24 hr than other statins, and has additional antioxidant property.

Side Effect 

side effects not differing from placebo. 

Notable side effects are: Gastrointestinal complaints and  headache are  usually  mild.  

Rashes and sleep disturbances are uncommon. 

Rise  in  serum transaminase can  occur,  but  liver  damage  is  rare

Monitoring of liver function is recommended.


Statins are the first choice drugs for primary hyperlipidaemias with raised LDL  and  total  CH  levels,  with  or  without  raised  TG  levels,  as  well  as  for secondary (diabetes, nephrotic syndrome) hypercholesterolaemia.


Cholestyramine and Colestipol: 

These are basic ion exchange resins supplied in the chloride form. 

They are neither digested nor absorbed in the gut: bind bile acids in the intestine interrupting their enterohepatic circulation. 

Faecal excretion of bile salts and CH (which is absorbed with the help of bile salts) is increased. 

This indirectly leads to enhanced hepatic metabolism of CH to bile acids. 

More LDL receptors are expressed on liver cells: clearance of plasma IDL, LDL and indirectly that of VLDL is increased. 

Resins have been shown to retard atherosclerosis, but are not popular clinically because they are unpalatable, inconvenient, have to be taken in  large doses, cause flatulence and otheg.i. symptoms, interfere with absorption of many drugs and have poor patient acceptability.




The  fibrates  (isobutyric  acid  derivatives)  primarily  activate  lipoprotein  lipase which is a key enzyme in the degradation of VLDL resulting in lowering of circulating TGs. 

This effect is exerted through peroxisome proliferator-activated receptor α (PPARα) that is a gene transcription regulating receptor expressed in and  fatty  acid  oxidation.  

PPARα  may  also  mediate  enhanced  LDL  recepto r expression  in   liver  seen  particularly  with  secon generation  fibrates  like bezafibrate,  fenofibrate.  Fibrates  decrease  hepatic  TG  synthesis  as  well.  

A peripheral effect reducing circulating free fatty acids has also been shown


This fibric acid derivative effectively lowers plasma TG level by enhancing breakdown and suppressing hepatic synthesis of TGs. Besides high efficacy in type III hyperlipoproteinemia, gemfibrozil has shown action in subjects with raised blood CH in addition. 

In the Helsinki Heart Study men without known CAD treated with gemfibrozil had a 34% reduction in fatal and nonfatal MI,  though  overall  mortality was  not  affected.  

That  these  benefits  extend  to secondary prevention of coronary events in men with existing CAD and low HDL- CH, has been demonstrated in another trial. 

Additional actions to decrease the level of clotting factor VII-phospholipid complex and promotion of fibrinolysis have been observed, which may contribute to the antiatherosclerotic effect. 


Gemfibrozil is completely absorbed orally, metabolized by glucuronidation and undergoes some enterohepatic circulation. It is excreted in urine; elimination is 1–2 hr.

Adverse effects: Common side effects are epigastric distress, loose motions. Skin rashes, body ache, eosinophilia, impotence, headache and blurred vision have been reported.  Myopathy  is   uncommon.  Gemfibrozil  +   statin   increases  risk  of myopathy. Incidence of gallstone is not increased as was seen with clofibrate.

It is contraindicated during pregnancy.




Nicotinic Acid (Niacin): It is a B group vitamin which in much higher doses reduces plasma lipids. This action is unrelated to its vitamin activitdecrease rapidly, followed by a modest fall in LDL-CH and total CH. A2050% reduction in plasma TGs and 1525% reduction in CH levels has been recorded.

Nicotinic acid is the most effective drug to raise HDL-CH, probably by decreasing rate of HDL destruction; a 20–35% increase is generally obtained. 

Relatively lower dose  suffices  to  raise  HDLCH. 

It  also  reduces  lipoprotein Lp  (a),  which  is considered more atherogenic. 

Nicotinic acid reduces production of VLDL in liver by inhibiting TG synthesis. 

Indirectly the VLDL degradation products IDL and LDL are also reduced.

No direct effect on CH and bile acid metabolism has been found. 

It inhibits intracellular lipolysis in adipose tissue and increases the activity of lipoprotein lipase that clears TGs.

Adverse effects: 

The large doses needed for hypolipidaemic action are poorly tolerated. 

Only about half of the patients are able to take the full doses. 

Nicotinic acid is a cutaneous vasodilator: marked flushing, heat and itching (especially in the blush area) occur after every dose. 

This is associated with release of PGD2 in the skin, and can be minimized by starting with a low dose taken with meals and gradually increasing as tolerance develops.

Dyspepsia is very common; vomiting and diarrhoea occur when full doses are given.

Peptic ulcer may be activated.


Dryness and hyperpigmentation of skin can be troublesome.


Other long-term effects are: Liver dysfunction and jaundice. 

Serious liver damage is the most important risk. 

Hyperglycemia, precipitation of diabetes (should not be used in diabetics).

It is contraindicated during pregnancy and in children.




It  is  a  novel drug  that  acts  by  inhibiting intestinal absorption of cholesterol and phytosterols. 

It  interferes with a specific CH transport protein NPC1L1 in the  intestinal mucosa  and reduces absorption of both dietary and biliary CH. 

There is compensatory increase in hepatic CH synthesis, but LDL-CH level is lowered by 15–20%. 

The enhanced CH synthesis can be blocked by statins, and the two drugs have synergistic LDL-CH lowering effect. Due to very poor aqueous solubility, ezetimibe is not absorbed as such. 

A fraction is absorbed after getting conjugated with glucuronic acid in the intestinal mucosa. 

This is secreted in bile and undergoes enterohepatic circulation to be mainly excreted in faeces. A plasma of 22 hours has been calculated.

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